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Abstract

A series of prodrugs of 2´, 3´-dideoxyinosine (didanosine, ddI) were

synthesized in an effort to alter different pharmacokinetic properties. The 5`OH function of ddI was esterified with three different carboxylic diacids. The diacids used was adipic acid, azelaic acid, dodecanedioic acid. The synthesis was optimized in order to develop a high yielding and regioselective synthesis.

Protein binding studies, using ultrafiltration, showed an increased protein binding compared to ddI itself. The relative protein binding for ddI was determined to 5 %. The relative binding for the ddI-derivatives were determined to 8-76% dependent on the length of the aliphatic chain.

A high-performance liquid chromatography (HPLC)-tandem mass

spectrometry method for the quantitative determination of ddI in rat plasma has been developed and partly validated. The biological samples were prepared using solid phase extraction.

The bioanalytical method was used to determine a pharmacokinetic profile after an i.v injection of ddI or ddI-prodrug in rats. The concentration of ddI deriving from ddI it self or ddI deriving from the azelaic acid monoester prodrug was followed as a function of time. The pharmacokinetic study showed that the azelaic acid monoester derivative of ddI was rapidly metabolized to ddI, probably quantitatively within 5 minutes.